Pharmaceutical Compositions

ABSTRACT

A pharmaceutical composition for inhalation comprising R(+) budesonide and one bronchodilators, and, optionally, one or more pharmaceutically acceptable excipients.

FIELD OF INVENTION

The present invention relates to pharmaceutical products andformulations comprising R(+) budesonide. More particularly the presentinvention relates to pharmaceutical products and formulations comprisingR(+) budesonide, which products and formulations are useful for thetreatment and/or prevention of respiratory, inflammatory or obstructiveairway disease. The present invention also relates to a process forpreparing the formulation according to the present invention,therapeutic uses thereof and methods of treatment employing the same.

BACKGROUND AND PRIOR ART

Asthma and chronic obstructive pulmonary disease (COPD) are the mostprevailing conditions which affect most people. Airflow obstruction isthe main characteristic feature in each of these airway diseases and themedications utilized in the treatment are also often similar.

The pathophysiology of asthma and related disorders involves varioussymptoms, including bronchoconstriction, inflammation of the airways,and increased mucous secretion, which results in wheezing, coughing andshortness of breath. A persistent or recurrent cough may exacerbate theproblem by causing further irritation and inflammation of the airways.Bronchoconstriction occurs due to bronchial smooth muscle spasm andairway inflammation with mucosal edema.

COPD is a severe respiratory condition that is increasing its prevalenceworldwide. In India, the estimated prevalence is about 12.36 million. Itis currently the fourth leading cause of death in the UK & US, andpredicted to rank third in the global impact of disease by the year2020.

COPD is a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The airflow obstruction isusually progressive and associated with an abnormal inflammatoryresponse of the lungs to noxious particles or gases, primarily caused bycigarette smoking. Although COPD affects the lungs it also producessignificant systemic consequences. COPD is associated with mucus hypersecretion, emphysema and bronchiolitis.

Therapy for the treatment or prevention of COPD and asthma currentlyincludes the use of bronchodilators such as beta₂-agonists,anticholinergics and steroids.

Inhaled bronchodilators are the foundation of pharmacotherapy for COPDbecause of their capacity to alleviate symptoms, decrease exacerbationsof disease and improve quality of life. These drugs also improve airflowlimitation and hyperinflation, thereby improving exercise tolerance. Inaddition bronchodilators may reduce respiratory muscle fatigue(controversial) and improve mucociliary clearance.

Long acting beta₂-agonists improve lung function, reduce symptoms andprotect against exercise-induced dyspnea in patients with asthma andCOPD. Long acting beta₂-agonists induce bronchodilation by causingprolonged relaxation of airway smooth muscle. In addition to prolongedbronchodilation, long acting beta₂-agonists (LABAs) exert other effectssuch as inhibition of airway smooth-muscle cell proliferation andinflammatory mediator release, as well as non smooth-muscle effects,such as stimulation of mucociliary transport, cytoprotection of therespiratory mucosa and attenuation of neutrophil recruitment andactivation.

Long acting beta₂-agonists reduce the symptoms that occur in the nightor the early morning which normally affect sleep patterns and reduce apatient's overall quality of life.

Further, use of a long acting beta₂-agonist reduces the frequency ofdrug administration.

Anticholinergic agents are also a first choice for the symptomatictreatment of patients with COPD.

Anticholinergic agents inhibit the muscarinic action of acetylcholine onstructure innervated by postganglionic cholinergic nerves. These agentstypically inhibit bronchoconstriction by relaxing the smooth muscles andcausing considerable bronchodilation.

Even though it is also known that beta₂-agonists and anticholinergicsprovide a symptomatic relief in bronchoconstriction, another componentof asthma, which is inflammation, requires separate treatment such aswith a steroid. Most of these inhaled corticosteroids need to beadministered in multiple dosage regimens.

Treatment with a corticosteroid/glucocorticoid is considered to be oneof the most potent and effective therapies currently available forpersistent asthma. Corticosteroids exhibit inhibitory effects oninflammatory cells and inflammatory mediators involved in thepathogenesis of respiratory disorders.

Corticosteroids are used in several forms, to treat many differentconditions. Because they reduce itching, swelling, redness, and allergicreactions, they are often used in treating skin problems, severeallergies, asthma, and arthritis.

Currently available corticosteroids include beclomethasone, budesonide,fluticasone, mometasone and triamcinolone.

Combination therapy of a long-acting beta₂-agonist, an anticholinergicand an inhaled corticosteroid improves pulmonary efficiency, reducesinflammatory response and provides symptomatic relief as compared tohigher doses of inhaled corticosteroid alone in patients affected byrespiratory disorders such as asthma and COPD. However, the selection ofa specific long-acting beta₂-agonist, a specific anticholinergic and aspecific inhaled corticosteroid plays a very important role informulation of a fixed dose combination.

Combination therapy also simplifies treatment of respiratory disorders,reduces the cost of treatment and provides control of the respiratorydisorders. Reducing the dose frequency to the minimum is a main step insimplifying COPD and asthma management for improving patient adherenceto the therapy.

US2009088408 discloses pharmaceutical compositions of anticholinergics,corticosteroids and betamimetics and their use in the treatment ofrespiratory diseases.

US20050042174 discloses combined doses of asthma medicaments such as acombination of doses of a beta₂-agonist, an anticholinergic agent and ananti-inflammatory steroid.

WO2006105401 discloses combination of an anticholinergic, acorticosteroid and a long acting beta₂-agonist for simultaneous andsequential administration in the prevention or treatment of arespiratory, inflammatory or obstructive airway disease.

WO2004028545 discloses a combination of a long-acting beta₂-agonist anda glucocorticosteroid in the treatment of fibrotic diseases.

However, uses of corticosteroids, especially in children, have beenlimited due to potential side effects. In children and teenagers, thesemedicines can stop or slow growth and affect the function of the adrenalglands (small glands located above each kidney, which secrete naturalcorticosteroids). Another possible problem for children is thatcorticosteroids may make infections such as chickenpox and measles moreserious.

The other side effects that are feared with corticosteroids includesuppression of the Hypothalamic-Pituitary-Adrenal (HPA) axis, effects onbone growth in children and on bone density in the elderly, ocularcomplications (cataract formation and glaucoma) and skin atrophy. Inolder people, corticosteroids may increase the risk of high bloodpressure and bone disease. Bone problems from corticosteroids areespecially likely in older women.

The benefits and risks of giving corticosteroids to children andteenagers should be thoroughly discussed with a physician. By adjustingthe doses and forms in which corticosteroids are given, a physician maybe able to lower the chance of unwanted side effects.

Some corticosteroids exist as enantiomers and exhibit chirality.Enantiomers are structurally identical compounds which differ only inthat, one isomer is a mirror image of the other and the mirror imagescannot be superimposed. This phenomenon is known as chirality. Althoughstructurally identical, enantiomers can have profoundly differenteffects in biological systems; one enantiomer may have a specificbiological activity while the other enantiomer may have no biologicalactivity at all, or may have an entirely different form of biologicalactivity.

Budesonide, a corticosteroid, has been widely used in the treatment ofchronic and asthmatic bronchitis due to its strong anti-inflammatoryaction, high selectivity and fewer side effects. The form in whichbudesonide is presently used is a racemic mixture. That is, it is amixture of optical isomers, called enantiomers R(+) and S(−), which arecharacterized by different strength and pharmacokinetic properties.

Budesonide, is chemically a mixture of two epimers 22R(+) and 22S(−)having a different configuration at the acetal 22-carbon atom. R(+)budesonide, which consists mainly of epimer 22R, is found to beclinically superior over the preparations consisting of a 1:1 mixture ofthe epimers.

The anti-inflammatory properties of R(+) isomer are nearly three timesas strong as compared to that of S(−) isomer. R(+) budesonide also showsgreater volume of distribution and plasma clearance. R(+) budesonide isvery well tolerated and does not cause any serious adverse effects.However as R(+) budesonide undergoes biotransformation more quickly thanS(−) isomer, the systemic action of R(+) budesonide is weaker ascompared to that of S(−) budesonide.

Budesonide is the mainstay in the treatment of respiratory andinflammatory or obstructive airway diseases. However most of theformulations containing budesonide available in the prior art containthe racemic mixture of budesonide.

Hence, there still remains a need to formulate pharmaceuticalcompositions comprising R(+) budesonide for inhalation having reducedside effects, and to formulate pharmaceutical compositions comprisingR(+) budesonide in combination with one or more bronchodilators forinhalation having reduced side effects.

OBJECT OF THE INVENTION

The object of the present invention is to provide novel pharmaceuticalcompositions for inhalation comprising R(+) budesonide and one or morebronchodilators for administration in the prevention or treatment ofrespiratory, inflammatory or obstructive airway disease.

Another object of the present invention is to provide novelpharmaceutical compositions for inhalation comprising R(+) budesonideand one or more bronchodilators for inhalation having reduced sideeffects in the prevention or treatment of respiratory, inflammatory orobstructive airway disease.

The compositions according to the invention may, of course, include oneor more pharmaceutically acceptable excipients.

Yet another object of the present invention is to provide a process forpreparing novel pharmaceutical compositions comprising R (+) budesonideand one or more bronchodilators for administration in the prevention ortreatment of respiratory, inflammatory or obstructive airway disease.

A further object of the present invention is to provide pharmaceuticalcompositions comprising R(+) budesonide and one or more bronchodilatorfor use in the prophylaxis or treatment of respiratory, inflammatory orobstructive airway disease.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention, there is provideda pharmaceutical composition comprising R(+) budesonide and one or morebronchodilators.

According to a second aspect of the present invention, there is provideda process for preparing a pharmaceutical composition comprising R(+)budesonide and one or more bronchodilators.

According to a third aspect of the present invention there is provided apharmaceutical composition comprising R(+) budesonide and one or morebronchodilators for use in treating disorders or conditions that respondto, or are prevented, ameliorated or eliminated by, the administrationof R(+) budesonide, and one or more bronchodilators.

DETAILED DESCRIPTION OF THE INVENTION

It has been found that the R(+) enantiomer of budesonide provides relieffrom bronchial disorders, while simultaneously reducing undesirable sideeffects commonly experienced by corticosteroid users. Further since theactive enantiomer is used, the dose required is also reduced as comparedto that of racemic budesonide, which reduced dose also contributes tothe reduction in undesirable side effects.

The present invention thus provides novel pharmaceutical compositionsfor inhalation comprising R(+) budesonide and one or morebronchodilators for administration in the prevention or treatment ofrespiratory, inflammatory or obstructive airway disease whilesimultaneously reducing undesirable side effects commonly experienced bycorticosteroid users.

According to the present invention, the optically pure R(+) isomer ofbudesonide may be administered alone, or in combination with one or morebronchodilators or other drug(s) for the treatment and/or prevention ofrespiratory, inflammatory or obstructive airway disease.

The other drugs may be selected from various classes of drugs commonlyused for respiratory diseases for example bronchodilators.

The present invention provides a pharmaceutical composition comprisingR(+) budesonide and one or more bronchodilators.

Bronchodilators used according to the present invention may bebeta₂-agonists and/or anticholinergics. As discussed, the selection of aspecific long-acting beta₂-agonist, an anticholinergic and inhaledcorticosteroid plays a very important role in formulation of fixed dosecombination.

The terms “beta₂-agonist agent” or “beta₂-agonist” or “anticholinergicagent” or “corticosteroids” are used in broad sense to include not onlythe beta₂-agonist or anticholinergic agent per se but also theirpharmaceutically acceptable salts, pharmaceutically acceptable solvates,pharmaceutically acceptable hydrates, pharmaceutically acceptableenantiomers, pharmaceutically acceptable derivatives, pharmaceuticallyacceptable enantiomers, pharmaceutically acceptable polymorphs,pharmaceutically acceptable prodrugs, etc.

The present invention also provides a pharmaceutical compositioncomprising R(+) budesonide and one or more beta₂-agonists.

According to the present invention, beta₂-agonists may comprise, one ormore, short acting beta₂-agonists, long acting beta₂-agonists or ultralong acting beta₂-agonists.

The beta₂-agonists that can be used, according to the present invention,include albuterol, levoalbuterol, terbutaline, pirbuterol, procaterol,metaproterenol, fenoterol, bitolterol mesylate, ritodrine, salmeterol,formoterol, arformoterol, carmoterol, bambuterol, clenbuterol,indacaterol, milveterol, vilanterol, olodaterol.

According to one embodiment of the present invention the pharmaceuticalcomposition may comprise R(+) budesonide and formoterol with one or morepharmaceutically acceptable excipients, R(+) budesonide and arformoterolwith one or more pharmaceutically acceptable excipients, R(+) budesonideand salmeterol with one or more pharmaceutically acceptable excipients.

According to another embodiment of the present invention thepharmaceutical composition may comprise R(+) budesonide, and carmoterolwith one or more pharmaceutically acceptable excipients.

According to yet another embodiment of the present invention thepharmaceutical composition may comprise R(+) budesonide, and indacaterolwith one or more pharmaceutically acceptable excipients.

The present invention also provides a pharmaceutical compositioncomprising R(+) budesonide and one or more anticholinergic agent.

Suitable anticholinergic agents include tiotropium, ipratropium andoxitropium.

According to one embodiment of the present invention the pharmaceuticalcomposition may comprise R(+) budesonide and tiotropium with one or morepharmaceutically acceptable excipients, or R(+) budesonide andipratropium with one or more pharmaceutically acceptable excipients, orR(+) budesonide and oxitropium with one or more pharmaceuticallyacceptable excipients.

The present invention also provides a pharmaceutical compositioncomprising R(+) budesonide and one or more beta-agonist and one or moreanticholinergic agents.

According to an embodiment of the present invention the pharmaceuticalcomposition may comprise R(+) budesonide, arformoterol and tiotropiumwith one or more pharmaceutically acceptable excipients, or R(+)budesonide, arformoterol and tiotropium with one or morepharmaceutically acceptable excipients or R(+) budesonide, tiotropiumand carmoterol with one or more pharmaceutically acceptable excipients,or R(+) budesonide, tiotropium and indacaterol with one or morepharmaceutically acceptable excipients.

A preferred beta₂-agonist for use in the present invention iscarmoterol.

Carmoterol, chemically known as8-hydroxy-5-(1-hydroxy-2-(N-(2-(4-methoxy phenyl)-1-methylethyl)amino)ethyl)-2(1H)-quinolinone hydrochloride salt is a long actingbeta₂-agonist characterized by having a rapid onset of action s,prolonged duration of action and also having a high selectivity towardsthe beta₂ adrenoreceptor. Furthermore carmoterol is more potent thanother long acting beta₂-agonists.

Another preferred beta₂-agonist for use in the present invention isindacaterol.

Indacaterol is chemically known as(R)-5-[2-[(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-hydroxyethyl]-8-hydroxy quinolin-2(1H)-one is a ultra long actingbeta₂-agonist. Furthermore indacaterol exhibits a longer duration ofaction as well as having a greater cardiovascular safety margin.

A preferred anticholinergic agent for use in the present invention istiotropium.

Tiotropium is chemically known as (1α, 2β, 4β, 5α, 7β)-7-[(hydroxydi-2-thienyl acetyl) oxy]-9, 9-di methyl-3-oxa-9-azonia tricyclo[3.3.1.0^(2,4)] nonane bromide monohydrate. Tiotropium has duration ofaction of up to 32 hours. Also tiotropium causes an improvement indyspnea and a reduction in the need for rescue therapy.

Tiotropium in combination with pulmonary rehabilitation (PR) isassociated with an increased exercise endurance time and producesclinically meaningful improvements in dyspnea and health status ascompared to PR alone in COPD patients.

Further, tiotropium is more potent than ipratropium in the treatment ofpatients with COPD in terms of the effect of lung function, dyspnea,exacerbation rates and health status.

The terms “carmoterol”, “indacaterol” and “tiotropium” are used in broadsense to include not only “carmoterol”, “indacaterol” and “tiotropium”per se but also their pharmaceutically acceptable salts,pharmaceutically acceptable solvates, pharmaceutically acceptablehydrates, pharmaceutically acceptable esters, pharmaceuticallyacceptable enantiomers, pharmaceutically acceptable derivatives,pharmaceutically acceptable polymorphs, pharmaceutically acceptableprodrugs, etc.

The term “R(+) budesonide” is used in broad sense to include not only“R(+) budesonide” per se but also its pharmaceutically acceptable salts,pharmaceutically acceptable solvates, pharmaceutically acceptablehydrates, pharmaceutically acceptable esters, pharmaceuticallyacceptable derivatives, pharmaceutically acceptable polymorphs,pharmaceutically acceptable prodrugs, etc.

In accordance with the present invention, the preferred beta₂-agonistsare: carmoterol, indacaterol, formoterol, arformoterol, salmeterol.

In accordance with the present invention, there preferredanticholinergics are: tiotropium, oxitropium, ipratropium

Particularly preferred compositions according to the invention arepharmaceutical compositions in which the beta₂-agonist comprises orconsists of carmoterol, indacaterol, formoterol, aformoterol,salmeterol, and the anticholinergic comprise or consists of tiotropium.

Particularly preferred compositions comprise:

-   -   R(+) budesonide, beta₂-agonist comprising carmoterol, an        anticholinergic comprising tiotropium, and, optionally, one or        more pharmaceutically acceptable excipients.    -   R(+) budesonide, beta₂-agonist consisting of carmoterol, an        anticholinergic consisting of tiotropium, and, optionally, one        or more pharmaceutically acceptable excipients.    -   R(+) budesonide, beta₂-agonist comprising indacaterol, an        anticholinergic comprising tiotropium, and, optionally, one or        more pharmaceutically acceptable excipients.    -   R(+) budesonide, beta₂-agonist consisting of indacaterol, an        anticholinergic consisting of tiotropium, and, optionally, one        or more pharmaceutically acceptable excipients.    -   R(+) budesonide, beta₂-agonist comprising formoterol, and,        optionally, one or more pharmaceutically acceptable excipients.    -   R(+) budesonide, beta₂-agonist consisting of formoterol, and,        optionally, one or more pharmaceutically acceptable excipients.    -   R(+) budesonide, beta₂-agonist comprising arformoterol, and,        optionally, one or more pharmaceutically acceptable excipients.    -   R(+) budesonide, beta₂-agonist consisting of arformoterol, and,        optionally, one or more pharmaceutically acceptable excipients.

According to the present invention, R(+) budesonide may be present inthe composition in the amount of about 80 mcg to about 640 mcg.

According to the present invention, carmoterol may be present in thecomposition in the amount of about 1 mcg to about 4 mcg.

According to the present invention, indacaterol may be present in thecomposition in the amount of about 50 mcg to about 800 mcg.

According to the present invention, tiotropium may be present in thecomposition in the amount of about 9 mcg to about 18 mcg.

We have found that the combination therapy of R(+) budesonide,tiotropium and carmoterol and the combination therapy of R(+)budesonide, tiotropium and indacaterol provide effective methods fortreating inflammatory and/or obstructive diseases of the respiratorytract, particularly COPD or asthma.

Furthermore, the combination of R(+) budesonide, tiotropium andcarmoterol and the combination of R(+) budesonide, tiotropium andindacaterol provide a rapid onset of action and improved control ofobstructive or inflammatory airway diseases, or reduction in theexacerbations of the diseases.

Another advantage of the combinations is that they facilitate thetreatment of an obstructive and inflammatory airway disease with asingle medicament.

We have further found that the combination of R(+) budesonide,tiotropium and carmoterol, and the combination of R(+) budesonide,tiotropium and indacaterol can each be administered once a day intherapeutically effective amounts.

Further this combination therapy provides for administration of thecombination by use of a single inhaler for patients with severe COPD whocurrently have to make use of multiple inhalers. This is particularlyimportant since COPD is a disease of the elderly who may get confusedbetween the inhalers and who also suffer from several combinedconditions such as heart disease, arthritis etc. and are receiving othermedications.

The pharmaceutical compositions of the present invention may beadministered by any suitable method used for delivery of drugs to therespiratory tract. The composition of the present invention may thus beadministered using metered dose inhalers (MDI), dry powder inhalers(DPI), nebulisers, nasal sprays, nasal drops, insufflation powders,sprays and spray patches.

Preferred embodiments of the invention comprise pharmaceuticalcompositions comprising R(+) budesonide and one or more bronchodilators,which compositions are used in the form of nebulisers, dry powderinhalers (DPI), nasal sprays, nasal drops, insufflation powders, spraysand spray patches; in a particularly preferred embodiment, compositionsare used in the form of metered dose inhalers (MDI).

The various dosage forms according to the present invention may comprisecarriers/excipients suitable for formulating the same.

The metered dose inhalation formulations, according to the presentinvention may comprise one or more pharmaceutically acceptableexcipients, such as HFC/HFA propellants, co-solvents, bulking agents,non volatile component, buffers/pH adjusting agents, surface activeagents, preservatives, complexing agents, lubricants, antioxidants orcombinations thereof.

In the context of the present invention, propellants are thosesubstances which, when mixed with the co-solvent(s), form a homogeneouspropellant system in which a therapeutically effective amount of amedicament can be dissolved. The HFC/HFA propellant must betoxicologically safe and must have a vapor pressure which is suitable toenable the medicament to be administered via a pressurized MDI.

According to the present invention the HFC/HFA propellants may comprise,one or more of 1,1,1,2-tetrafluoroethane (HFA-134(a)),1,1,1,2,3,3,3,-heptafluoropropane (HFA-227), HFC-(difluoromethane),HFC-143(a) (1,1,1-trifluoroethane), HFC-134 (1,1,2,2-tetrafluoroethane),HFC-152a (1,1-difluoroethane) and such other propellants which may beknown to the person having a skill in the art.

In the context of the present invention, the co-solvent is any solventwhich is miscible in a formulation in the amount desired and which, whenadded, provides a formulation in which the medicament can be dissolved.The function of the co-solvent is to increase the solubility of themedicament and the excipients in the formulation.

According to the present invention the co-solvent may comprise one ormore of C₂-C₆ aliphatic alcohols, such as but not limited to ethylalcohol and isopropyl alcohol; glycols such as but not limited topropylene glycol, polyethylene glycols, polypropylene glycols, glycolethers, and block copolymers of oxyethylene and oxypropylene; and othersubstances, such as but not limited to glycerol, polyoxyethylenealcohols, and polyoxyethylene fatty acid esters; hydrocarbons such asbut not limited to n-propane, n-butane, isobutane, n-pentane,iso-pentane, neo-pentane, and n-hexane; and ethers such as but notlimited to diethyl ether.

Suitable surfactants may be employed in the aerosol solution formulationof the present invention, which surfactants may serve to stabilize thesolution formulation and improve the performance of valve systems withina metered dose inhaler.

According to the present invention the surfactant may comprise one ormore ionic and I or non-ionic surfactant, but not limited to oleic acid,sorbitan trioleate, lecithin, isopropylmyristate, tyloxapol,polyvinylpyrrolidone polysorbates such as polysorbate 80, vitaminE-TPGS, and macrogol hydroxystearates such asmacrogol-15-hydroxystearate. In the context of the present invention,the non-volatile component is all the suspended or dissolvedconstituents that would be left after evaporation of the solvent.

According to the present invention, the non-volatile component maycomprise one or more of monosaccharides such as but not limited toglucose, arabinose; disaccharides such as lactose, maltose;oligosaccharides and polysaccharides such as but not limited todextrans; polyalcohol such as but not limited to glycerol, sorbitol,mannitol, xylitol; salts such as but not limited to potassium chloride,magnesium chloride, magnesium sulphate, sodium chloride, sodium citrate,sodium phosphate, sodium hydrogen phosphate, sodium hydrogen carbonate,potassium citrate, potassium phosphate, potassium hydrogen phosphate,potassium hydrogen carbonate, calcium carbonate and calcium chloride.

Suitable bulking agents may be employed in the metered dose inhalationformulations of the present invention.

According to the present invention, the bulking agent may comprise oneor more saccharides, including monosaccharides, disaccharides,polysaccharides and sugar alcohols such as arabinose, glucose, fructose,ribose, mannose, sucrose, terhalose, lactose, maltose, starches, dextranor mannitol.

Suitable buffers or pH adjusting agents may be employed in the metereddose inhalation formulations of the present invention.

According to the present invention, the buffer or the pH adjusting agentmay comprise one or more of organic or inorganic acids such as but notlimited to citric acid, ascorbic acid, hydrochloric acid, sulfuric acid,nitric acid, or phosphoric acid.

Suitable preservatives may be employed in aerosol solution formulationsof the present invention to protect such formulations from contaminationwith pathogenic bacteria.

According to the present invention, the preservative may comprise one ormore of benzalkonium chloride, benzoic acid, benzoates such as sodiumbenzoate and such other preservatives which may be known to the personhaving a skill in the art.

Suitable complexing agents may be employed in aerosol solutionformulations of the present invention, which complexing agents arecapable of forming complex bonds.

According to the present invention, the complexing agent may compriseone or more of but not limited to sodium EDTA or disodium EDTA.

A further preferred embodiment of the present invention can be where thecomposition is in the form of insufflatable powder. R(+) budesonide incombination with one or more bronchodilator may be mixed with inertcarrier substances or drawn up onto inert carrier substances to forminsufflatable powders.

A dry powder insufflation composition according to the present inventioncan be administered by the use of an insufflator, which can produce afinely divided cloud of the dry powder. The insufflator preferably isprovided with means to ensure administration of a substantiallypre-determined amount of a formulation or product as provided by thepresent invention. The powder may be used directly with an insufflator,which is provided with a bottle or container for the powder, or thepowder may be filled into a capsule or cartridge, such as a gelatincapsule, or other single dose device adapted for administration. Theinsufflator preferably has means to open the capsule or other dosedevice.

A further preferred embodiment of the present invention can be where thecomposition is in the form of dry powder inhaler (DPI). R(+) budesonidein combination with one or more bronchodilator may be mixed with inertcarrier substances or drawn up onto inert carrier substances to form drypowder inhalation formulations.

Carrier substances suitable for forming the insufflation powders or drypowder inhalation formulations of the present invention include but arenot limited to sugars/sugar alcohols such as glucose, saccharose,lactose and fructose, starches or starch derivatives, oligosaccharidessuch as dextrins, cyclodextrins and their derivatives,polyvinylpyrrolidone, alginic acid, tylose, silicic acid, cellulose,cellulose derivatives (for example cellulose ether), sugar alcohols suchas mannitol or sorbitol, calcium carbonate, calcium phosphate, lactose,lactitol, dextrates, dextrose, maltodextrin, saccharides includingmonosaccharides, disaccharides, polysaccharides; sugar alcohols such asarabinose, ribose, mannose, sucrose, trehalose, maltose and dextran.

In another embodiment of the present invention the composition may be inthe form of a nebuliser formulation.

Nebulisation therapy has an advantage over other inhalation therapy,since it is easy to use and does not require co-ordination or mucheffort. It also works much more rapidly than medicines taken by mouth.

For nebulisers, the composition according to the present invention maycomprise suitable excipients such as osmotic agents, pH regulatorsbuffering agent, wetting agent and complexing agents in a suitablevehicle.

Osmotic agents, which may be used in nebuliser formulations according tothe present invention include sodium chloride, potassium chloride, zincchloride, calcium chloride and mixtures thereof. Other suitable osmoticagents include, but are not limited to, mannitol, glycerol, dextrose andmixtures thereof.

The pH of a nebuliser formulation may be adjusted by the addition ofpharmacologically acceptable acids. Pharmacologically acceptableinorganic acids or organic acids may be used for this purpose. Examplesof preferred inorganic acids are selected from the group consisting ofhydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid andphosphoric acid and mixtures thereof. Examples of particularly suitableorganic acids are selected from the group consisting of ascorbic acid,citric acid, malic acid, tartaric acid, maleic acid, succinic acid,fumaric acid, acetic acid, formic acid and propionic acid and mixturesthereof.

Complexing agents that may be used in nebuliser formulations accordingto the present invention include editic acid (EDTA) or one of the knownsalts thereof, e.g. sodium EDTA or disodium EDTA dihydrate (sodiumedetate).

Wetting agents that may be used in nebuliser formulations according tothe present invention include sodiumdioctylsulfosuccinate; polysorbatessuch as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80,polysorbate 65, polysorbate 85; sorbitan fatty acid esters such as Span20, Span 40, Span 60 Span 80, Span 120; sodium lauryl sulfate;polyethoxylated castor oil; polyethoxylated hydrogenated castor oil andmixtures thereof.

Anti-microbial preservative agent may also be added for multi-dosepackages.

The formulation according to the present invention may be included insuitable containers provided with means enabling the application of thecontained formulation to the respiratory tract.

The dry powder inhalation formulations of the present invention mayeither be encapsulated in capsules of gelatin or HPMC, or in blisters.Alternatively, the dry powder inhalation formulations may be containedin a reservoir either in a single dose or multi-dose dry powderinhalation device.

Alternatively, the dry powder inhalation formulations may be suspendedin a suitable liquid vehicle and packed in an aerosol container alongwith suitable propellants or mixtures thereof.

Further, the dry powder inhalation formulations may also be dispersed ina suitable gas stream to form an aerosol composition.

The metered dose inhalation formulations of the present invention may bepacked in plain aluminium cans or in SS (stainless steel) cans. Someaerosol drugs tend to adhere to the inner surfaces, i.e. walls, of thecans and valves. This can lead to the patient getting significantly lessthan the prescribed amount of the active agent upon each activation of ametered dose inhaler. Coating the inner surface of the container with asuitable polymer can reduce this adhesion problem. Suitable coatingsinclude fluorocarbon copolymers such as FEP-PES (fluorinated ethylenepropylene and poly ether sulphone) and PFA-PES (perfluoro alkoxy alkaneand poly ether sulphone), epoxy and ethylene. Alternatively, the innersurfaces of the cans may be anodized, plasma treated or plasma coated.

It will be understood by a person skilled in the art that thepharmaceutical composition, according to the present invention, mayfurther comprise (i.e. in addition to the bronchodilator, i.e., thebeta₂-agonist and/or the anticholinergic) one or more active(s) selectedfrom antihistamines, antiallergics or leukotriene antagonist or theirpharmaceutically acceptable salts, solvates, tautomers, derivatives,enantiomers, isomers, hydrates, prodrugs or polymorphs thereof.

The present invention also provides a process to manufacture thecompositions according to the present invention.

Thus the present invention provides a process of preparing a metereddose inhalation formulation which process comprises admixing more ormore pharmaceutically acceptable carriers and/or excipients with theactives (e.g. R(+) budesonide and one or more bronchodilators) and thepropellant, and optionally providing the formulation in precrimped cans.

The present invention also provides a process of preparing a dry powderinhalation formulation which process comprises admixing of one or morepharmaceutically acceptable carriers and/or excipients with the actives(e.g. R(+) budesonide and one or more bronchodilator) and providing theformulation as a dry powder inhaler.

The present invention also provides a process of preparing an inhalationsolution which process comprises dissolving the drugs, optionallychelating agents, osmotic agents and any other suitable ingredients inthe vehicle and adjusting the pH using a suitable pH adjusting agent.

The present invention further provides a method for the treatment in amammal, such as a human, for treating respiratory, inflammatory orobstructive airway disease such as COPD and asthma, which methodcomprises administration of a therapeutically effective amount of apharmaceutical composition according to the present invention. Themethod of treatment may be characterized in that R(+) budesonide and oneor more bronchodilators are administered once a day in therapeuticallyeffective amounts, e.g. R(+) budesonide, tiotropium and carmoterol orR(+) budesonide, tiotropium and indacaterol are administered once a dayin therapeutically effective amounts.

Furthermore, the present invention provides pharmaceutical compositionscomprising R(+) budesonide and one or more bronchodilators for use inthe prophylaxis or treatment of respiratory, inflammatory or obstructiveairway disease.

The following examples are for the purpose of illustration of theinvention only and are not intended in any way to limit the scope of thepresent invention.

EXAMPLE 1

Sr. No. Ingredients Qty/Can 1. R (+) Budesonide 16 mg 2. Arformoteroltartarate 0.48 mg 3. HFA134a 9.6 g

Process:

(1) R(+) Budesonide and Arformoterol tartarate were dispersed with thepropellant.

(2) The suspension obtained in step (1) was filled in precrimped cans.

EXAMPLE 2

Sr. No. Ingredients Qty/Can 1. R (+) Budesonide 16 mg 2. Arformoteroltartarate 0.48 mg 3. 2% Ethanol 0.22 g 4. 0.22% Lecithin 0.0003 mg 5.HFA227 11.0 g

Process:

(1) Lecithin was dispersed in ethanol.

(2) R(+) Budesonide and Arformoterol tartarate were dispersed in themixture as obtained in step (1).

(3) The drug suspension was mixed with propellant HFA277.

(4) The suspension obtained in step (3) was filled in precrimped cans.

EXAMPLE 3

Sr. No. Ingredients Qty/Can 1. R (+) Budesonide 16 mg 2. Arformoteroltartarate 0.48 mg 3. HFA227 11.2 g

Process:

(1) R(+) Budesonide and Arformoterol tartarate were dispersed with thepropellant.

(2) The suspension obtained in step (1) was filled in precrimped cans.

EXAMPLE 4

Sr. No. Ingredients Qty/Can 1. R (+) Budesonide 16 mg 2. Arformoteroltartarate 0.48 mg 3. 0.3% PEG 1000 33.6 mg 4. 0.001% PVP K25 0.11 mg 5.HFA227 11.2 g

Process:

(1) PVP was dispersed in PEG.

(2) R(+) Budesonide and Arformoterol tartarate were dispersed in themixture as obtained in step (1).

(3) The drug suspension was mixed with propellant HFA277.

(4) The suspension obtained in step (3) was filled in precrimped cans.

EXAMPLE 5

Sr. No. Ingredients Qty/Can 1. R (+) Budesonide 16 mg 2. Formoterolfumarate 0.96 mg 3. HFA134a 9.6 g

Process:

(1) R(+) Budesonide and Formoterol fumarate were dispersed with thepropellant.

(2) The suspension obtained in step (1) was filled in precrimped cans.

EXAMPLE 6

Sr. No. Ingredients Qty/Can 1. R (+) Budesonide 16 mg 2. Formoterolfumarate 0.96 mg 3. 2% Ethanol 0.22 g 4. 0.22% Lecithin 0.0003 mg 5.HFA227 11.0 g

Process:

(1) Lecithin was dispersed in ethanol.

(2) R(+) Budesonide and Formoterol fumarate were dispersed in themixture as obtained in step (1).

(3) The drug suspension was mixed with propellant HFA277

(4) The suspension obtained in step (3) was filled in precrimped cans.

EXAMPLE 7

Sr. No. Ingredients Qty/Can 1. R (+) Budesonide 16 mg 2. Formoterolfumarate 0.96 mg 3. HFA227 11.2 g

Process:

(1) R(+) Budesonide and Formoterol fumarate were dispersed with thepropellant.

(2) The suspension obtained in step (1) was filled in precrimped cans.

EXAMPLE 8

Sr. No. Ingredients Qty/Can 1. R (+) Budesonide 16 mg 2. Formoterolfumarate 0.96 mg 3. 0.3% PEG 1000 33.6 mg 4. 0.001% PVP K25 0.11 mg 5.HFA227 11.2 g

Process:

(1) PVP was dispersed in PEG.

(2) R(+) Budesonide and Formoterol fumarate were dispersed in themixture as obtained in step (1).

(3) The drug suspension was mixed with propellant HFA277.

(4) The suspension obtained in step (3) was filled in precrimped cans.

EXAMPLE 9

Sr. No. Ingredients Qty/Spray 1. R (+) Budesonide 100 mcg  2. Tiotropium9 mcg 3. Carmoterol 1 mcg 4. HFA134A or HFA227 q.s

Process:

(1) R(+) Budesonide, Tiotropium and Carmoterol were homogenized with apart quantity of HFA.

(2) The suspension obtained in step (1) was transferred to the mixingvessel where the remaining quantity of HFA was added.

(3) The resulting suspension was mixed, recirculated and filled intopre-crimped aluminum cans.

EXAMPLE 10

Sr. No. Ingredients Qty/Spray 1. R (+) Budesonide 100 mcg  2. Tiotropium9 mcg 3. Carmoterol 1 mcg 4. Lactose 100% of the drug 5. HFA134A orHFA227 q.s.

Process:

(1) R(+) Budesonide, Tiotropium and Carmoterol were homogenized withlactose and a part quantity of HFA.

(2) The suspension obtained in step (1) was transferred to the mixingvessel where the remaining quantity of HFA was added.

(3) The resulting suspension was mixed, recirculated and filled in intopre-crimped aluminum cans.

EXAMPLE 11

Sr. No. Ingredients Qty/Spray 1. R (+) Budesonide 100 mcg  2. Tiotropium9 mcg 3. Carmoterol 1 mcg 4. PEG400/1000 0.3% of total formulation 5.PVP K 25 0.001% of total formulation 6. HFA134A or HFA227 q.s.

Process:

(1) PVP was dissolved in PEG and part quantity of HFA.

(2) The solution obtained in step (1) was transferred to a mixingvessel.

(3) R(+) Budesonide, Tiotropium and Carmoterol were homogenized with apart quantity of HFA.

(4) The suspension obtained in step (3) was transferred to the mixingvessel where remaining quantity of HFA was added.

(5) The resulting total suspension was mixed, recirculated and filled ininto pre-crimped aluminum cans.

EXAMPLE 12

Sr. No. Ingredients Qty/Spray 1. R (+) Budesonide 100 mcg  2. Tiotropium9 mcg 3. Carmoterol 1 mcg 4. Ethanol 15-20% of total formulation 5.Glycerol 1% of total formulation 6. HCL (0.08N) pH 2.5-3.5 7. HFA134aq.s.

Process:

(1) Glycerol was dissolved in ethanol and required quantity of HCl wasadded.

(2) R(+) Budesonide, Tiotropium and Carmoterol were dissolved in thesolution obtained in step (1).

(3) The resulting solution was transferred to the mixing vessel whereHFA was added.

(4) The resulting solution was mixed, recirculated and filled in intopre-crimped aluminum cans.

EXAMPLE 13

Sr. No. Ingredients Qty/Spray 1. R (+) Budesonide 100 mcg  2. Tiotropium9 mcg 3. Carmoterol 1 mcg 4. Ethanol 15-20% of total formulation 5. HCL(0.08N) pH 2.5-3.5 6. HFA134a q.s.

Process:

(1) Required quantity of HCl was added to ethanol.

(2) R(+) Budesonide, Tiotropium and Carmoterol were dissolved in thesolution obtained in step (1).

(3) The resulting solution was transferred to the mixing vessel whereHFA was added.

(4) The resulting solution was mixed, recirculated and filled in intopre-crimped aluminum cans.

EXAMPLE 14

Sr. No. Ingredients Qty/Spray 1. R (+) Budesonide 100 mcg  2. Tiotropium9 mcg 3. Carmoterol 1 mcg 4. Ethanol 15-20% of total formulation 5.Glycerol 1% of total formulation 6. Citric acid anhydrous pH 2.5-3.5 7.HFA134a q.s.

Process:

(1) Required quantity of citric acid and glycerol was added to ethanol.

(2) R(+) Budesonide, Tiotropium and Carmoterol were dissolved in thesolution obtained in step (1).

(3) The resulting solution was transferred to the mixing vessel whereHFA was added.

(4) The resulting solution was mixed, recirculated and filled in intopre-crimped aluminum cans.

EXAMPLE 15

Sr. No. Ingredients Qty/Spray 1. R (+) Budesonide 100 mcg  2. Tiotropium9 mcg 3. Carmoterol 1 mcg 4. Ethanol 15-20% of total formulation 5.Citric acid anhydrous pH 2.5-3.5 6. HFA134a q.s.

Process:

(1) Required quantity of citric acid was added to ethanol.

(2) R(+) Budesonide, Tiotropium and Carmoterol were dissolved in thesolution obtained in step (1).

(3) The resulting solution was transferred to the mixing vessel whereHFA was added.

(4) The resulting solution was mixed, recirculated and filled in intopre-crimped aluminum cans.

EXAMPLE 16

Sr. No. Ingredients Qty/Spray 1. R (+) Budesonide 100 mcg 2. Tiotropium 9 mcg 3. Carmoterol  1 mcg 4. Ethanol 1-2% of total formulation 5.Lecithin 0.02% of the drug 6. HFA134a or HFA227 q.s.

Process:

(1) Required quantity of lecithin was added to ethanol.

(2) Tiotropium and Carmoterol were homogenized with part quantity of HFAand transferred to the mixing vessel.

(3) R(+) Budesonide was homogenized with the solution obtained from step(1) and part quantity of HFA.

(4) The suspension obtained in step (4) was transferred to the mixingvessel where the remaining quantity of HFA was added.

(5) The resulting suspension is then mixed, recirculated and filled ininto pre-crimped aluminum cans.

EXAMPLE 17

Sr. No. Ingredients Qty/Spray 1. R (+) Budesonide 100 mcg 2. Tiotropium 9 mcg 3. Carmoterol  1 mcg 4. Ethanol 1-2% of total formulation 5.Oleic acid 0.02-5% of the drug 6. HFA134a or HFA227 q.s.

Process:

(1) Required quantity of oleic acid was added to ethanol.

(2) Tiotropium and Carmoterol were homogenized with part quantity ofFIFA and transferred to the mixing vessel.

(3) R(+) Budesonide was homogenized with the solution obtained from step(1) and part quantity of HFA.

(4) The suspension obtained in step (4) was transferred to the mixingvessel where remaining quantity of HFA was added.

(5) The resulting suspension is then mixed, recirculated and filled ininto pre-crimped aluminum cans.

EXAMPLE 18

No. Ingredients Qty/Unit 1 R (+) Budesonide  0.160 mg 2 Carmoterol 0.002 mg 3 Tiotropium Bromide Monohydrate 0.0225 mg 4 Lactosemonohydrate 24.8155 mg  Total 25.000 mg

Process:

(1) R(+) Budesonide, Caromoterol, Tiotropium Bromide Monohydrate weresifted with a part quantity of lactose.

(2) The cosift of step (1) was then sifted with the remaining quantityof lactose and blended.

(3) The blend of step (2) was then filled in capsules.

EXAMPLE 19

No. Ingredients Qty/Unit 1 R (+) Budesonide  0.640 mg 2 Carmoterol 0.004 mg 3 Tiotropium Bromide Monohydrate  0.0225 mg 4 Lactosemonohydrate 24.3335 mg Total 25.0000 mg

Process:

(1) R(+) Budesonide, Caromoterol, Tiotropium Bromide Monohydrate weresifted with a part quantity of lactose.

(2) The cosift of step (1) was then sifted with the remaining quantityof lactose and blended.

(3) The blend of step (2) was then filled in capsules.

EXAMPLE 20

Sr. No. Ingredients Qty/Spray 1. R (+) Budesonide 100 mcg 2. Tiotropium 9 mcg 3. Indacaterol  50 mcg 4. HFA134A or HFA227 q.s

Process:

(1) R(+) Budesonide, Tiotropium and Indacaterol were homogenized with apart quantity of HFA.

(2) The suspension obtained in step 1 was transferred to the mixingvessel where the remaining quantity of HFA was added.

(3) The resulting suspension was mixed, recirculated and filled in intopre-crimped aluminum cans.

EXAMPLE 21

Sr. No. Ingredients Qty/Spray 1. R (+) Budesonide 100 mcg 2. Tiotropium 9 mcg 3. Indacaterol  50 mcg 4. Lactose 100% of the drug 5. HFA134A orHFA227 q.s.

Process:

(1) R(+) Budesonide, Tiotropium and Indacaterol were homogenized withlactose and a part quantity of HFA.

(2) The suspension obtained in step 1 was transferred to the mixingvessel where the remaining quantity of HFA was added.

(3) The resulting suspension was mixed, recirculated and filled in intopre-crimped aluminum cans.

EXAMPLE 22

Sr. No. Ingredients Qty/Spray 1. R (+) Budesonide 100 mcg 2. Tiotropium 9 mcg 3. Indacaterol  50 mcg 4. PEG400/1000 0.3% of total formulation5. PVP K 25 0.001% of total formulation 6. HFA134A or HFA227 q.s.

Process:

(1) PVP was dissolved in PEG and part quantity of HFA.

(2) The solution obtained in Step 1 was transferred to a mixing vessel.

(3) R(+) Budesonide, Tiotropium and Indacaterol were homogenized with apart quantity of HFA.

(4) The suspension obtained in step 3 was transferred to the mixingvessel where remaining quantity of HFA was added.

(5) The resulting total suspension was mixed, recirculated and filled ininto pre-crimped aluminum cans.

EXAMPLE 23

Sr. No. Ingredients Qty/Spray 1. R (+) Budesonide 100 mcg 2. Tiotropium 9 mcg 3. Indacaterol  50 mcg 4. Ethanol 15-20% of total formulation 5.Glycerol 1% of total formulation 6. HCL (0.08N) pH 2.5-3.5 7. HFA134aq.s.

Process:

(1) Glycerol was dissolved in ethanol and required quantity of HCl wasadded.

(2) R(+) Budesonide, Tiotropium and Indacaterol were dissolved in thesolution obtained in step (1).

(3) The resulting solution was transferred to the mixing vessel whereHFA was added.

(4) The resulting solution was mixed, recirculated and filled in intopre-crimped aluminum cans.

EXAMPLE 24

Sr. No. Ingredients Qty/Spray 1. R (+) Budesonide 100 mcg 2. Tiotropium 9 mcg 3. Indacaterol  50 mcg 4. Ethanol 15-20% of total formulation 5.HCL (0.08N) pH 2.5-3.5 6. HFA134a q.s.

Process:

(1) Required quantity of HCl was added to ethanol.

(2) R(+) Budesonide, Tiotropium and Indacaterol were dissolved in thesolution obtained in step (1).

(3) The resulting solution was transferred to the mixing vessel whereHFA was added.

(4) The resulting solution was mixed, recirculated and filled in intopre-crimped aluminum cans.

EXAMPLE 25

Sr. No. Ingredients Qty/Spray 1. R (+) Budesonide 100 mcg 2. Tiotropium 9 mcg 3. Indacaterol  50 mcg 4. Ethanol 15-20% of total formulation 5.Glycerol 1% of total formulation 6. Citric acid anhydrous pH 2.5-3.5 7.HFA134a q.s.

Process:

(1) Required quantity of citric acid and glycerol was added to ethanol.

(2) R(+) Budesonide, Tiotropium and Indacaterol were dissolved in thesolution obtained in step (1).

(3) The resulting solution was transferred to the mixing vessel whereHFA was added.

(4) The resulting solution was mixed, recirculated and filled in intopre-crimped aluminum cans.

EXAMPLE 26

Sr. No. Ingredients Qty/Spray 1. R (+) Budesonide 100 mcg 2. Tiotropium 9 mcg 3. Indacaterol  50 mcg 4. Ethanol 15-20% of total formulation 5.Citric acid anhydrous pH 2.5-3.5 6. HFA134a q.s.

Process:

1) Required quantity of citric acid was added to ethanol.

2) R(+) Budesonide, Tiotropium and Indacaterol were dissolved in thesolution obtained in step (1).

3) The resulting solution was transferred to the mixing vessel where HFAwas added.

4) The resulting solution was mixed, recirculated and filled in intopre-crimped aluminum cans.

EXAMPLE 27

Sr. No. Ingredients Qty/Spray 1. R (+) Budesonide 100 mcg 2. Tiotropium 9 mcg 3. Indacaterol  50 mcg 4. Ethanol 1-2% of total formulation 5.Lecithin 0.02 of the API 6. HFA134a or HFA227 q.s.

Process:

1) Required quantity of lecithin was added to ethanol.

2) Tiotropium and Indacaterol were homogenized with part quantity of HFAand transferred to the mixing vessel.

3) R(+) Budesonide was homogenized with the solution obtained from step(1) and part quantity of HFA.

4) The suspension obtained in step (4) was transferred to the mixingvessel where remaining quantity of HFA was added.

5) The resulting suspension is then mixed, recirculated and filled ininto pre-crimped aluminum cans.

EXAMPLE 28

Sr. No. Ingredients Qty/Spray 1. R (+) Budesonide 100 mcg 2. Tiotropium 9 mcg 3. Indacaterol  50 mcg 4. Ethanol 1-2% of total formulation 5.Oleic acid 0.02-5% of the drug 6. HFA134a or HFA227 q.s.

Process:

1) Required quantity of oleic acid was added to ethanol.

2) Tiotropium and Indacaterol were homogenized with part quantity ofFIFA and transferred to the mixing vessel.

3) R(+) Budesonide was homogenized with the solution obtained from step(1) and part quantity of HFA.

4) The suspension obtained in step (4) was transferred to the mixingvessel where the remaining quantity of HFA was added.

5) The resulting suspension is then mixed, recirculated and filled ininto pre-crimped aluminum cans.

EXAMPLE 29

No. Ingredients Qty/Unit 1 R (+) Budesonide  0.160 mg 2 Indacaterolmaleate 0.1944 mg 3 Tiotropium Bromide Monohydrate 0.0225 mg 4 Lactosemonohydrate IP/Ph. Eur/NF 24.6231 mg  Total 25.000 mg

Process:

(1) R(+) Budesonide, Indacaterol maleate, Tiotropium Bromide Monohydratewere sifted with a part quantity of lactose.

(2) The cosift of step (1) was then sifted with the remaining quantityof lactose and blended.

(3) The blend of step (2) was then filled in capsules.

EXAMPLE 30

No. Ingredients Qty/Unit 1 R (+) Budesonide  0.640 mg 2 Indacaterolmaleate  0.3888 mg 3 Tiotropium Bromide Monohydrate  0.0225 mg 4 Lactosemonohydrate IP/Ph. Eur/NF 23.9487 mg Total 25.0000 mg

Process:

(1) R(+) Budesonide, Indacaterol maleate, Tiotropium Bromide Monohydratewere sifted with a part quantity of lactose.

(2) The cosift of step 1 was then sifted with the remaining quantity oflactose and blended.

(3) The blend of step 2 was then filled in capsules.

It will be readily apparent to one skilled in the art that varyingsubstitutions and modifications may be made to the invention disclosedherein without departing from the spirit of the invention. Thus, itshould be understood that although the present invention has beenspecifically disclosed by the preferred embodiments and optionalfeatures, modification and variation of the concepts herein disclosedmay be resorted to by those skilled in the art, and such modificationsand variations are considered to fall within the scope of the invention.

It is to be understood that the phraseology and terminology used hereinis for the purpose of description and should not be regarded aslimiting. The use of “including,” “comprising,” or “having” andvariations thereof herein is meant to encompass the items listedthereafter and equivalents thereof as well as additional items.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referencesunless the context clearly dictates otherwise. Thus, for example,reference to “an excipient” includes a single excipient as well as twoor more different excipients, and the like.

1. A pharmaceutical composition comprising R(+) budesonide and one ormore bronchodilators, and, optionally, one or more pharmaceuticallyacceptable excipients.
 2. A pharmaceutical composition according toclaim 1, wherein R(+) budesonide in an amount ranging from 80-640 mcg.3. A pharmaceutical composition according to claim 1, wherein thebronchodilator comprises one or more beta₂-agonists.
 4. A pharmaceuticalcomposition according to claim 3, wherein the beta₂-agonist is selectedfrom albuterol, levoalbuterol, terbutaline, pirbuterol, procaterol,metaproterenol, fenoterol, bitolterol mesylate, ritodrine, salmeterol,formoterol, arformoterol, carmoterol, bambuterol, clenbuterol,indacaterol, milveterol, vilanterol, olodaterol or a combinationthereof.
 5. A pharmaceutical composition according to claim 3, whereinthe beta₂-agonist comprises formoterol.
 6. A pharmaceutical compositionaccording to claim 3, wherein the beta₂-agonist comprises arformoterol.7. A pharmaceutical composition according to claim 3, wherein thebeta₂-agonist comprises salmeterol.
 8. A pharmaceutical compositionaccording to claim 3, wherein the beta₂-agonist comprises carmoterol. 9.A pharmaceutical composition according to claim 3, wherein carmoterol isin an amount ranging from 1 mcg-4 mcg.
 10. A pharmaceutical compositionaccording to claim 3, wherein the beta₂-agonist comprises indacaterol.11. A pharmaceutical composition according to claim 3, whereinindacaterol is in an amount ranging from 50 mcg-800 mcg.
 12. Apharmaceutical composition according to claim 1, wherein thebronchodilator comprises one or more anticholinergics.
 13. Apharmaceutical composition according to claim 12, wherein theanticholinergic is selected from tiotropium, ipratropium, oxitropium andcombinations thereof.
 14. A pharmaceutical composition according toclaim 12, wherein the anticholinergic comprises tiotropium.
 15. Apharmaceutical composition according to claim 12, wherein tiotropium isin an amount ranging from 9 mcg-18 mcg.
 16. A pharmaceutical compositionaccording to claim 12, wherein the anticholinergic comprises oxitropium.17. A pharmaceutical composition according to claim 12, wherein theanticholinergic comprises ipratropium.
 18. A pharmaceutical compositionaccording to claim 1, wherein the bronchodilator comprises one or morebeta₂-agonists and/or one or more anticholinergics.
 19. A pharmaceuticalcomposition according to claim 1, comprising R(+) budesonide andformoterol .
 20. A pharmaceutical composition according to claim 1,comprising R(+) budesonide and arformoterol
 21. A pharmaceuticalcomposition according to claim 1, comprising R(+) budesonide, tiotropiumand carmoterol.
 22. A pharmaceutical composition according to claim 1,comprising R(+) budesonide, tiotropium and indacaterol.
 23. Apharmaceutical composition according to claim 1, wherein R(+) budesonideand beta₂-agonists along with any excipients are formulated in a singlepharmaceutical composition.
 24. A pharmaceutical composition accordingto claim 1, wherein R(+) budesonide and anticholinergics along with anyexcipients are formulated in a single pharmaceutical composition.
 25. Apharmaceutical composition according to claim 1, wherein beta₂-agonistsand anticholinergics along with any excipients are formulated in asingle pharmaceutical composition.
 26. A pharmaceutical compositionaccording to claim 1, wherein R(+) budesonide, beta₂-agonists andanticholinergics along with any excipients are formulated in a singlepharmaceutical composition.
 27. A pharmaceutical composition accordingto claim 1, formulated as an inhalation composition.
 28. Apharmaceutical composition according to claim 1, formulated for use in ametered dose inhaler.
 29. A pharmaceutical composition according toclaim 27, further comprising a propellant.
 30. A pharmaceuticalcomposition according to claim 27, further comprising an excipientselected from a cosolvent, an antioxidant, a surfactant, a bulking agentand a lubricant.
 31. A pharmaceutical composition according to claim 1,formulated for use as a dry powder inhalation formulation.
 32. Apharmaceutical composition according to claim 31, further comprising atleast one finely divided pharmaceutically acceptable carrier suitablefor use in dry powder inhalation formulations.
 33. A combinationcomposition according to claim 32, wherein said carrier includes asaccharide and/or a sugar alcohol.
 34. A combination compositionaccording to claim 1, formulated for use as an inhalation solution. 35.A combination composition according to claim 34, further comprising anexcipient selected from a wetting agent, osmotic agent, a pH regulator,a buffering agent and a complexing agent, provided in a pharmaceuticallyacceptable vehicle.
 36. A pharmaceutical composition according to claim1, formulated for inhalation, for use as a nasal spray, for use as nasaldrops, for use as an insufflation powder, or for use as a spray patch.37. A pharmaceutical composition according to claim 1, for once dailyadministration.
 38. A pharmaceutical composition according to claim 1 ,further comprising one or more active(s) selected from antihistamines,antiallergics or leukotriene antagonist or their pharmaceuticallyacceptable salts, solvates, tautomers, derivatives, enantiomers,isomers, hydrates, prodrugs or polymorphs thereof.
 39. A process formanufacturing a pharmaceutical composition according to claim 1,comprising combining R(+) budesonide with one or more bronchodilatorsand one or more optional pharmaceutically acceptable excipients. 40.(canceled)
 41. (canceled)
 42. (canceled)
 43. (canceled)
 44. A method ofprophylaxis or treatment of a respiratory, inflammatory or obstructiveairway disease, comprising administering a therapeutically effectiveamount of a pharmaceutical composition according to claim 1, to apatient in need thereof.
 45. A method according to claim 44, whereinsaid pharmaceutical composition is administered once daily.
 46. A methodaccording to claim 44, wherein the disease is COPD or asthma. 47.(canceled)
 48. (canceled)